Cannabinoid Antagonist Drug Discrimination in Nonhuman Primates
| Autor: | Shakiru O. Alapafuja, Shan Jiang, Ani S. Zakarian, Brian D. Kangas, Jack Bergman, Alexandros Makriyannis, Kiran Vemuri, Spyros P. Nikas |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Agonist Cannabinoid receptor medicine.drug_class medicine.medical_treatment Drug Evaluation Preclinical Pharmacology 03 medical and health sciences Discrimination Psychological 0302 clinical medicine Rimonabant medicine Animals Inverse agonist Benzopyrans Cannabinoid Receptor Antagonists Saimiri Cannabinoid Receptor Agonists Drug Substitution business.industry Antagonist Substance Withdrawal Syndrome Discontinuation Nabilone Disease Models Animal 030104 developmental biology Behavioral Pharmacology Molecular Medicine Cannabinoid business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | J Pharmacol Exp Ther |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.119.261818 |
| Popis: | Despite a growing acceptance that withdrawal symptoms can emerge following discontinuation of cannabis products, especially in high-intake chronic users, there are no Food and Drug Administration (FDA)–approved treatment options. Drug development has been hampered by difficulties studying cannabis withdrawal in laboratory animals. One preclinical approach that has been effective in studying withdrawal from drugs in several pharmacological classes is antagonist drug discrimination. The present studies were designed to examine this paradigm in squirrel monkeys treated daily with the long-acting CB(1) agonist AM2389 (0.01 mg/kg) and trained to discriminate the CB(1) inverse agonist/antagonist rimonabant (0.3 mg/kg) from saline. The discriminative-stimulus effects of rimonabant were both dose and time dependent and, importantly, could be reproduced by discontinuation of agonist treatment. Antagonist substitution tests with the CB(1) neutral antagonists AM4113 (0.03–0.3 mg/kg), AM6527 (0.03–1.0 mg/kg), and AM6545 (0.03–1.0 mg/kg) confirmed that the rimonabant discriminative stimulus also could be reproduced by CB(1) antagonists lacking inverse agonist action. Agonist substitution tests with the phytocannabinoid ∆(9)-tetrahydrocannabinol (0.1–1.0 mg/kg), synthetic CB(1) agonists nabilone (0.01–0.1 mg/kg), AM4054 (0.01–0.03 mg/kg), K2/Spice compound JWH-018 (0.03–0.3 mg/kg), FAAH-selective inhibitors AM3506 (0.3–5.6 mg/kg), URB597 (3.0–5.6 mg/kg), and nonselective FAAH/MGL inhibitor AM4302 (3.0–10.0 mg/kg) revealed that only agonists with CB(1) affinity were able to reduce the rimonabant-like discriminative stimulus effects of withholding daily agonist treatment. Although the present studies did not document physiologic disturbances associated with withdrawal, the results are consistent with the view that the cannabinoid antagonist drug discrimination paradigm provides a useful screening procedure for examining the ability of candidate medications to attenuate the interoceptive stimuli provoked by cannabis discontinuation. SIGNIFICANCE STATEMENT: Despite a growing acceptance that withdrawal symptoms can emerge following the discontinuation of cannabis products, especially in high-intake chronic users, there are no FDA-approved pharmacotherapies to assist those seeking treatment. The present studies systematically examined cannabinoid antagonist drug discrimination, a preclinical animal model that is designed to appraise the ability of candidate medications to attenuate the interoceptive effects that accompany abrupt cannabis abstinence. |
| Databáze: | OpenAIRE |
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